The present invention relates to the use of CCK-B antagonists for the treatment of sleep disorders.
Cholecystokinins (CCK) and gastrin are structurally related peptides which exist in gastrointestinal tissue and in the central nervous system. Cholecystokinins include CCK-33, a neuropeptide of thirty-three amino acids in its originally isolated form, its carboxyl terminal octapeptide, CCK-8 (also a naturally occurring neuropeptide), and 39- and 12-amino acid forms. Gastrin occurs in 34-, 17- and 14- amino acid forms, with the minimum active sequence being the C-terminal tetrapeptide, Trp-Met-Asp-Phe-NH2 (CCK-4) which is the common structural element shared by both CCK and gastrin.
CCK and gastrin are gastrointestinal hormones and neurotransmitters in the neural and peripheral systems and perform their respective biological roles by binding to particular receptors located at various sites throughout the body. There are at least two subtypes of cholecystokinin receptors termed CCK-A and CCK-B and both are found in the periphery and in the central nervous system.
The CCK-A receptor, commonly referred to as the xe2x80x9cperipheral-typexe2x80x9d receptor, is primarily found in the pancreas, gallbladder, ileum, pyloric sphincter and on vagal afferent nerve fibers. Type-A CCK receptors are also found in the brain in discrete regions and serve to provide a number of CNS effects. Due to the ability of CCK-8 and Type-A CCK-selective agonists to suppress food intake in several animal species, considerable interest has been generated toward the development of new substances which function as Type-A receptor-selective CCK agonists in order to serve as anorectic agents.
The CCK-B or gastrin receptors are found in peripheral neurons, gastrointestinal smooth muscle and gastrointestinal mucosa, most notably in parietal cells, ECL cells, D cells and chief cells. CCK-B receptors also predominate in the brain and have been implicated in the regulation of anxiety, arousal and the action of neuroleptic agents.
Sleep disorders are the disturbances of sleep that affect the ability to fall and or stay asleep, which involve sleeping too much or result in abnormal behaviour associated with sleep. There are two types of sleep which cyclical and are marked by characteristic electro-encephalograms (EEG) and other changes including eye movements. The first phase of sleep which in normal sleep accounts for 75-80% of total sleep time is referred to as the non-rapid-eye-movement (NREM) type and this is characterised by slow waves on the EEG. The second sleep type (REM-rapid eye movement) which follows NREM is characterised by EEG low voltage fast activity and occurs 5 to 6 times during a normal nights sleep. In sleep disorders the balance of the two types of sleep is disturbed.
We have now found compounds which exhibit an antagonist activity at the CCK-B receptor influence sleep patterns and are therefore useful for the treatment of sleep disorders.
Thus the present invention provides for the use of a compound having an antagonist activity at the CCK-B receptor in the manufacture of a medicament for the treatment of sleep disorders.
Examples of suitable CCK-B antagonists for use in the treatment of sleep disorders includes the 1,4-benzodiazepine derivatives having CCK-B antagonist activity described in EPA 167919, EPA 284256, EPA 434360. EPA 434364, EPA 434369, EPA 514125, EPA 51426, EPA 514133, EPA 508796, EPA 508797, EPA 508798, EPA 508799, EPA 523845, EPA 523846, EPA 559170, EPA 549039, WO 9211246, WO 93032078, WO 9308175, WO 9307131, WO 9317011, WO 9319053, WO 9308175. WO 9413648 WO 9403437. The subject matter of the above identified published patent applications are incorporated herein by reference. Within the 1,4 benzodiazepine derivative disclosed above a particularly useful class of CCK-B antagonists include representated by the general formula (I). 
and N-oxides thereof and pharmaceutically acceptable salts thereof
wherein
R1 represents C1-6 alkyl (optionally substituted by hydroxyl C1-4 alkoxy, COR4, CONR5R6 or C3-7 cycloalkyl) or C3-7 cycloalkyl;
R4 represents C1-6 alkoxy or optionally substituted phenyl;
R6 is methyl or ethyl and R6 is phenyl or R5 and R6 together form a C4-C6 alkylene chain, which may be substitued by 1 or 2 alkyl groups;
R2 represents a substituted or unsubstituted phenyl group (wherein the substitutents may be 1 or 2 of halo, C1-4 alkyl, nitro, cyano, trifluoromethyl, trifluoromethoxy, C1-4alkylthio or (CH2)n R7 wherein R7 is hydroxy, C1-4 alkoxy, CO2R8, NR8R9, SO2NR8COR10, CONR8SO2R10, or R7 represents a tetrazolyl, carboxamidotetrazolyl, 3-trifluoromethyl-1,2-4-triazolyl or 5-oxo-1,2,4 oxadiazolyl group, which groups may be substituted on one of the nitrogen atoms by a C1-4alkyl group;
R8 represents hydrogen of a C1-4alkyl group;
R9 independently represents hydrogen or a C1-4alkyl group or the group SO2CF3;
R10 represents C1-4alkyl;
R3 represents C1-6 alkyl C3-7 cycloalkyl, phenyl (optionally substituted by halogen), azacycloalkyl or alkyl substituted by an amino, C1-4 alkylamino, diC1-4alkylamino, morpholino, pyrrolidino, piperidino, hexamethylene, thiomorpholino or N-methyl piperazino group; X represents hydrogen or halogen.
Within this class particularly preferred compounds include those wherein R1 is alkyl e.g. methyl, isopropyl or CH2COR4 wherein R4 is optionally substituted phenyl or the group CH2CO NR5R6 wherein R5 is methyl or ethyl and R6 is an optionally substituted phenyl group or NR5R6 represents a pyrrolidino, or piperidino group, which groups may be optionally substituted by one or 2 alkyl groups; and R3 is alkyl, cycloalkyl, phenyl optionally substituted by fluorine or a group selected from 